Complications of atherosclerosis, most notably coronary heart disease and myocardial infarction, are a major cause of morbidity and mortality in Western populations. Of the many risk factors that have been associated with the development of atherosclerosis and coronary heart disease, an elevated concentration of low density lipoproteins (LDLs) in the plasma appears to be one of the most irn~ 0rtant. l.~ The concentration of LDL in plasma is determined by the rate at which LDL enters the plasma relative to the rate at which LDL is cleared from plasma by the various organs of the body. LDLs circulating in the plasma are formed during the metabolism of triglyceride-rich very low density lipoprotein^^,^(VLDL), which in turn are secreted by the liver (Fig. 1). The primary function of VLDL is to transport triglyceride from the liver to peripheral sites of utilization and storage. Most of the triglyceride in the VLDL particle is hydrolyzed by lipoprotein lipase, an enzyme located on the surface of endothelial cells in skeletal muscle, heart, and adipose tissue. VLDL are thereby converted to VLDL remnants, a portion of which is rapidly cleared by LDL receptors in the liver, while the remainder are metabolized to LDL, apparently as a result of the continued action of lipoprotein lipase and hepatic triglyceride lipase. In most animal species, the majority of VLDL is rapidly cleared from plasma as VLDL remnants, and plasma LDL concentrations are low.'In humans, however, 80 to 90% of VLDL is ultimately metabolized to LDL particles, which have a much slower t~ rnover.~ LDL is taken up into tissues by at least two distinct transport processes. One of these is receptor dependent and involves the interaction of apolipoprotein (apo) BlOO of LDL with specific receptors on the cell surface followed by clustering of these receptors in coated pits and internalization via an endosoma1 In the fibroblast, the LDL receptor is synthesized on membrane-bound ribosomes, glycosylated in the Golgi apparatus, and then inserted into the plasma membrane. Within 10 minutes, LDL receptors gather into coated pits that invaginate to form endocytic vesicle^.^ Multiple endocytic vesicles fuse to form larger endosomes where the LDL particle dissociates from its receptor as a result of a fall in the pH within the endosome. The LDL receptor, along with a number of other receptors, clusters in a portion of the endosomal membrane that pinches off and returns the receptors to the cell surface while the LDL particles are delivered to lysosomes where they are hydrolyzed to amino acids, fatty acids, and cholesterol. The liberated cholesterol is used to support membrane biosynthesis and also serves as a precursor for bile acids and steroid hormones in the liver and endocrine organs, respectively.